Summary: The p53 tumor suppressor gene is mutated or inactivated in a majority of human cancers. p53 is a multifunctional protein that contributes to both activation and repression of gene transcription as well as DNA repair and has been implicated in the control of a number of cellular pathways including differentiation, apoptosis, and growth arrest. The ability of p53 to bind DNA and transactivate gene transcription is believed to be critical to its tumor suppressor function. We are currently evaluating the requirement for p53 mediated transactivation in keratinocyte models of differentiation and neoplastic progression, utilizing transgenic mice expressing a p53 mutant under the endogenous promoter that is capable of binding DNA but defective in the ability to transactivate gene expression. p53 transactivation can also be modulated by other proteins. It has recently become clear that p53 is a member of a gene family, including p63 and p73, with overlapping functions. p63 and p73 are expressed as a number of splice variants, some of which lack the tranactivation domain and can function to block p53 mediated transcription. We are defining the differential expression and functional significance of these isoforms under varying physiologic conditions using murine epidermis as a model of squamous epithelium.